Low-Dose Interleukin-2 for Steroid-Refractory Chronic Graft-Vs.-Host Disease: Phase 2 and Long Term Efficacy, Safety and Immune Correlates

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 41-41
Author(s):  
John Koreth ◽  
Haesook T. Kim ◽  
Kyle T. Jones ◽  
Carol G Reynolds ◽  
Marie J Chammas ◽  
...  
Keyword(s):  
Clinical Response ◽  
Research Funding ◽  
Low Dose ◽  
Phase 1 ◽  
Interleukin 2 ◽  
Phase 2 ◽  
Rapid Rise ◽  
Clinical Responses

Abstract Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) results from incomplete reconstitution of immune tolerance. CD4+CD25+FOXP3+ regulatory T cells (Treg) are required for tolerance and function as dominant suppressors of innate and adaptive immune effector cells. In our prior phase 1 cGVHD study daily subcutaneous (SC) low-dose interleukin-2 (IL-2) for 8 weeks induced Treg expansion in vivo and objective clinical responses in 12 of 23 evaluable participants (NEJM 2011). We now report on a phase 2 trial of daily low-dose SC IL-2 at 1x106 IU/m2/d for 12 weeks in steroid-refractory cGVHD. The study comprised 35 HCT recipients (51% male, 91% HLA-matched PBSC grafts). Median participant age was 51 years (range, 22-72). Median time from HCT and from cGVHD onset to start of IL-2 treatment was 616 days (range, 270-2145) and 252 days (range, 28-1880) respectively. Participants had a median of 4 cGVHD organ sites (range, 1-7), and 2 concurrent cGVHD therapies (range, 1-3) at enrollment. The median baseline prednisone dose was 20 mg (range, 2.5-50). The median follow-up in survivors was 21 months (range, 4-35). 12 week low dose IL-2 was well tolerated: 2 participants withdrew and 5 required IL-2 dose reduction for constitutional AE (n=6) and thrombocytopenia (n=1); 1 had Gr 3 infection (bacteremia); and none experienced relapse. At week 12, objective cGVHD responses (PR) were documented in 21 of 33 evaluable participants (64%). Two (6%) had cGVHD progression. cGVHD response sites included skin (n=9), joint/fascia/muscle (n=4), liver (n=7), lung (n=3), and GI tract (n=4). Overall 2-year OS/PFS was 91% (responders 94%; non-responders 83%). 23 participants with clinical benefit (PR or SD with minor response) proceeded on extended IL-2 therapy. Immunologically, low dose IL-2 induced a >4-fold increase in median Treg count/µL (p<0.001): a rapid rise from a baseline of 17.1 (Q1-Q3, 8.6-40.6) to a week 4 peak of 137.9 (Q1-Q3, 51.8-188) and subsequent stabilization with a week 12 count of 104.1 (Q1-Q3, 53.9-167.1). No significant change in CD4 conventional T cell (Tcon), CD8 T cell, or CD20 B cell count was noted. NK cell count increased >3-fold (p<0.001). The median Treg:Tcon ratio increased >4-fold (p<0.001): a rapid rise from baseline of 0.06 (Q1-Q3, 0.05-0.13) to a week 2 peak of 0.35 (Q1-Q3, 0.26-0.48) that remained elevated through a week 12 ratio of 0.31 (Q1-Q3, 0.27-0.39) (Figure). Treg count and Treg:Tcon ratio declined during 4 weeks off IL-2 and rose thereafter on restarting IL-2. Clinical responders were younger (50 vs. 61.5 years, p=0.01) and initiated IL-2 earlier (499 vs. 903 days post HCT, p=0.015). Responders had a higher median Treg:Tcon ratio at study baseline (0.09 vs. 0.06, p=0.052) and at week 1 of IL-2 (0.3 vs. 0.14, p=0.01). Combining phase 1 and 2 data, Treg:Tcon ratios of ≥0.07 at baseline and ≥0.2 at week 1 of IL-2 were highly predictive of clinical response (p=0.007; p=0.0013 respectively). The combined phase 1 and 2 extended IL-2 cohort comprised 35 participants with a median follow up of 16.2 months (range, 4.1-66.8), with 20 and 12 participants receiving over 1 and 2 years of IL-2 respectively. Extended daily low dose IL-2 was well tolerated, and only 4 participants had Gr 3 AEs deemed IL-2 related: lung infection (n=1), arthralgia (n=1), and injection site induration (n=2). 5 participants required IL-2 dose reduction and 1 had hematologic malignancy relapse. Clinical responses were typically sustained during taper of concomitant immunosuppression. Treg augmentation persisted for the duration of IL-2 therapy. Tcon count slowly recovered to normal levels and Treg:Tcon ratio gradually normalized over a 2 year period. There was no change in CD8 count. The median steroid taper was 50% (range, -20-100). In summary, daily low dose IL-2 therapy induced profound Treg enhancement, and clinical responses in over half of refractory cGVHD patients. Early clinical response predictors suggest IL-2 is more effective earlier in the cGVHD course and when starting numbers of Treg are higher. Sustained clinical and immunologic response during extended IL-2 was documented. Long term tolerance induction with daily low dose IL-2 is a promising and feasible strategy. Optimizing IL-2 clinical response by further augmenting Treg and the Treg;Tcon ratio early in the course of cGVHD is worth exploring. Figure 1 Figure 1. Disclosures Koreth: Prometheus Laboratories Inc: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Takeda Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Low-dose Interleukin-2 for immune tolerance. Chen:Bayer Pharmaceuticals, Inc.: Other, Research Funding. Avigan:Astex Pharmaceuticals : Research Funding.

Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: Long Term Outcomes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 292-292 ◽  
Author(s):  
Joseph M Connors ◽  
Stephen Ansell ◽  
Steven I. Park ◽  
Michelle A. Fanale ◽  
Anas Younes
Keyword(s):  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Phase 1 ◽  
Brentuximab Vedotin ◽  
Advanced Stage ◽  
Newly Diagnosed ◽  
Genetics Research

Background: The ABVD regimen containing doxorubicin, bleomycin, vinblastine, and dacarbazine is a common standard of care for the frontline treatment of advanced stage Hodgkin lymphoma (Santoro 1987; Duggan 2003) and is curative for the majority of patients; however, up to 30% of patients require a secondary therapy. Hodgkin Reed-Sternberg cells of classical HL (cHL) typically express CD30. In a pivotal phase 2 trial brentuximab vedotin (A, ADCETRIS®), comprised of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE) induced an objective response rate (ORR) of 75% and complete response rate (CR) of 34% in highly treatment-refractory patients with cHL (Younes 2012). Methods: We conducted a phase 1, open-label, multicenter study to evaluate the safety and efficacy of A when administered in combination with standard therapy (ABVD) or the same regimen without bleomycin (AVD) (Younes 2013). Adult patients with newly diagnosed advanced stage (II bulky, II B, III or IV; 80% stage III or IV) received doses of 0.6, 0.9, or 1.2 mg/kg A with standard doses of ABVD or 1.2 mg/kg with AVD, depending on cohort assignment on Days 1 and 15 of each 28-day cycle for up to 6 cycles of therapy. Previously we reported that among patients assessable for response 95% of patients given ABVD+A achieved a CR, as did 96% of patients given AVD+A. None of 26 patients given AVD+A but 11 of 25 (44%) given ABVD+A experienced pulmonary toxicity, including 2 deaths, establishing that A cannot be safely combined with bleomycin. In this current study we provide the long term survival and safety data on patients enrolled in the phase 1 trial. Results: In total 51 patients were assigned to either ABVD+A (n=25) or AVD+A (n=26). 1 patient who withdrew from the trial during the first cycle of ABVD+A is excluded from this analysis and 1 patient who received 3 cycles of ABVD+A, then withdrew, then received 3 cycles of ABVD alone and 2 patients who died during treatment (pulmonary toxicity) are included (total n=50). Median follow-up from diagnosis for the 24 patients treated with ABVD+A is 41 months (range 9-51 months) and for the 26 patients treated with AVD+A, 31 months (range 9-35 months). All 26 patients treated with AVD+A have been followed longer than the longest time to relapse (7 months). 45 patients remain in first CR and 5 treatment failures have occurred: 4 in the ABVD+A cohort (2 toxic deaths; 2 relapses (9 and 23 months from diagnosis)) and 1 after AVD+A (7 months from diagnosis). 3y-failure-free survival (3y-FFS) is 83% and 96% for ABVD+A and AVD+A, respectively, and 3y-overall survival (3y-OS), is 92% and 100%. No additional toxic deaths have occurred in follow-up. Conclusions: These updated outcomes reflecting the impact of adding brentuximab vedotin (1.2 mg/kg) to standard doses of AVD for classical Hodgkin lymphoma, demonstrating 96% 3y-FFS and 100% 3y-OS with no major unexpected toxicity, strongly support the current large international trial comparing AVD-A (AVD+1.2mg/kg brentuximab vedotin) to standard ABVD (ECHELON-1, clinicaltrials.gov NCT01712490), which may identify a new, less toxic gold standard treatment for advanced stage classical Hodgkin lymphoma. Disclosures Connors: Seattle Genetics: Research Funding. Off Label Use: brentuximab vedotin in phase 1 trial. Ansell:Seattle Genetics: Research Funding. Park:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding. Fanale:Seattle Genetics: Research Funding. Younes:Seattle Genetics: Research Funding; Millennium/Takeda: Research Funding.

scholarly journals Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4552-4552 ◽  
Author(s):  
Michael J. Mauro ◽  
Jorge E. Cortes ◽  
Andreas Hochhaus ◽  
Michele Baccarani ◽  
Timothy P. Hughes ◽  
...  
Keyword(s):  
Research Funding ◽  
Progressive Disease ◽  
Phase 1 ◽  
Efficacy And Safety ◽  
Employment Equity ◽  
Long Term Follow Up ◽  
T315i Mutation ◽  
Equity Ownership

Abstract Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib is the only approved oral TKI that inhibits the T315I mutant, which is uniformly resistant to other TKIs. Here we report long-term follow-up of the efficacy and safety of ponatinib in pts with the T315I mutation at baseline from the Phase 1 (Ph1) and PACE trials. Methods: The Ph1 trial (NCT01207440) evaluated safety and anti-leukemic activity of ponatinib (2-60 mg qd) in pts with CML or Ph+ ALL (N=81); the PACE trial (NCT00660920) evaluated efficacy and safety of ponatinib (45 mg qd) in CML and Ph+ ALL pts (N=449) resistant/intolerant to dasatinib or nilotinib or with the T315I mutation. Data reported are for pts with the T315I mutation at baseline, detected by Sanger sequencing at a central lab. Results: The Ph1 and PACE trials included 19 (29%) and 128 (29%) pts with the T315I mutation, respectively. Median age and median time since diagnosis were 47 and 2.7 years for Ph1, and 53 and 3.6 years for PACE.Pts were heavily pretreated: 89% in Ph1 and 84% in PACE had received ≥2 prior TKIs. As of Jan 6, 2014, median follow-up was 42 (1-59) months in Ph1, and 20 (0.1-40) months in PACE; 58% Ph1 (92% CP-CML) and 33% PACE (52% CP-CML) pts remained on study. Most-common reasons for discontinuation: administrative decision (16%) and progressive disease (16%) for Ph1, and progressive disease (31%) and adverse events (AEs; 13%) for PACE. Of the pooled chronic phase (CP)-CML pts, 75%, 72%, and 61% achieved MCyR, CCyR, and MMR, respectively, with deeper responses (MR4, MR4.5) observed in over a third of the pts (Table). MaHR was achieved in 58%, 27% and 38% of pooled AP-CML, BP-CML and Ph+ ALL pts, respectively. For Ph 1 CP-CML pts, 3-year CCyR duration estimates were 80%. For PACE CP-CML pts, 2-year MCyR/CCyR duration, PFS and OS estimates were 93%/79%, 72% and 82%, respectively. Only 1 CP-CML pt in PACE lost MCyR and 1 transformed to AP-CML. For AP-CML, BP-CML, and Ph+ ALL, estimated OS/PFS at 2 years was 69%/54%, 14%/10%, and 10%/N/A, respectively. The most frequent treatment-emergent AEs (TEAEs) observed in Ph1 CP-CML pts were dry skin (83%), rash (83%), arthralgia (75%), fatigue (75%), headache (67%), abdominal pain (58%), hypertension (58%), hypertriglyceridemia (58%), myalgia (58%), and nausea (58%). None of the 19 serious TEAEs that occurred in Ph1 CP-CML pts occurred in >1 pt. The most common (≥25%) TEAEs in PACE CP-CML pts were rash (48%), dry skin (42%), headache (41%), abdominal pain (39%), nausea (36%), constipation (33%), fatigue (33%), thrombocytopenia (28%), myalgia (28%), hypertension (27%), arthralgia (25%), and upper respiratory tract infection (25%). Most common (≥5 %) serious TEAEs in PACE CP-CML pts were acute myocardial infarction (8%), pancreatitis (8%), atrial fibrillation (6%), coronary artery disease (6%), congestive cardiac failure (5%), pneumonia (5%), cerebral infarction (5%), pyrexia (5%), increased lipase (5%), and dyspnea (5%). Arterial thrombotic events occurred in 1 (8%) Ph1, and 20 (31%) PACE pts. Venous thromboembolic events occurred in 1 (8%) Ph1, and 3 (5%) PACE pts. Despite the higher median dose intensity for T315I CP-CML pts (38 vs 30.8 mg/day overall CP-CML) in PACE, the safety profiles were similar. For CP-CML pts in PACE, responses achieved by 12 months were generally maintained after dose reduction primarily to manage AEs: 100% maintained MCyR; 100% maintained CCyR, and 79% maintained MMR. Conclusions: In Ph+ leukemia pts with the T315I mutation, where effective treatment options are limited, ponatinib continued to exhibit deep and durable responses with up to 6 years follow-up. Dose reductions to manage AEs did not impact maintenance of cytogenetic responses. The response rates and safety profile of T315I pts were comparable to, if not better than, those observed in the overall population of refractory CML and Ph+ ALL pts in ponatinib clinical trials. Table. Responses at Any Time in Ponatinib Treated Pts with T315I Mutation Phase 1 PACE Phase 1 and PACE Pooled n (%) n (%) n (%) CP-CML N=12 N=64 N=76 MCyR 11 (92) 46 (72) 57 (75) CCyR 10 (83) 45 (70) 55 (72) MMR 9 (75) 37 (58) 46 (61) MR4 7 (58) 25 (39) 32 (42) MR4.5 4 (33) 21 (33) 25 (33) AP-CML N=1 N=18 N=19 MaHR 0 11 (61) 11 (58) BP-CML N=2 N=24 N=26 MaHR 0 7 (29) 7 (27) Ph+ ALL N=4 N=22 N=26 MaHR 2 (50) 8 (36) 10 (38) Disclosures Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

scholarly journals LO58: Long-term outcomes among emergency department syncope patients: a systematic review

CJEM ◽  
2018 ◽  
Vol 20 (S1) ◽  
pp. S27-S27
Author(s):  
C. Leafloor ◽  
P. Jiho Hong ◽  
L. Sikora ◽  
J. Elliot ◽  
M. Mukarram ◽  
...  
Keyword(s):  
Systematic Review ◽  
Emergency Department ◽  
Phase 1 ◽  
Adverse Outcomes ◽  
Cochrane Central Register ◽  
Phase 2 ◽  
Long Term Outcomes ◽  
One Year

Introduction: Approximately 50% of patients discharged from the Emergency Department (ED) after syncope have no cause found. Long-term outcomes among syncope patients are not well studied, to guide physicians regarding outpatient testing and follow-up. The objective of this study was to conduct a systematic review for long-term (one year) outcomes among ED patients with syncope. We aim to use the results of this review to guide us in prospective analysis of one year outcomes with our large database of syncope patients. Methods: We searched Cochrane Central Register of Controlled Trials, Medline and Medline in Process, PubMed, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) from the inception to June, 2017. We included studies that reported long-term outcomes among adult ED patients (16 years or older) with syncope. We excluded studies on pediatric patients, and studies that included syncope mimickers: pre-syncope, seizure, intoxication, loss of consciousness after head trauma. We also excluded case reports, letters to the editor and review articles. Outcomes included death, syncope recurrence requiring hospitalization, arrhythmias and procedural interventions for arrhythmias. We selected articles based on title and abstract review during phase-1 and conducted full article review during phase-2. Meta-analysis was performed by pooling the outcomes using random effects model (RevMan v.5.3; Cochrane Collaboration). Results: Initial literature search generated 2094 articles after duplicate removal. 50 articles remained after phase-1 (=0.85) and 16 articles were included in the systematic review after phase-2 (=0.86). The 16 included studies enrolled a total of 44,755 patients. Pooled analysis at 1-year follow-up showed the following outcomes: 7% mortality; 14% recurrence of syncope requiring hospitalization; one study reported that 0.6% of patients had a pacemaker inserted; and two studies reported 0.8 11.5% of patients suffered new arrhythmias. Conclusion: An important proportion of ED patients with syncope suffer outcomes at 1-year. Appropriate follow-up is needed to prevent long-term adverse outcomes. Further prospective research to identify patients at risk for long-term important cardiac outcomes and death is needed.

Assessment of Early Cytogenetic Response As a Predictor of Long-Term Clinical Outcomes in a Phase 1/2 Study of Bosutinib in Chronic Phase CML.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2798-2798 ◽  
Author(s):  
Jorge E Cortes ◽  
Tim H Brümmendorf ◽  
H. Jean Khoury ◽  
Andreas Hochhaus ◽  
Jane Apperley ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Satellite Symposia ◽  
Time Point

Abstract Abstract 2798 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). In an open-label, phase 1/2 trial BOS 500 mg/d demonstrated clinical activity and manageable toxicity in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance/intolerance to imatinib (IM; Blood 2011;118:4567-76) and possibly dasatinib (DAS) and/or nilotinib (NI; Blood 2012;119:3403-12). This retrospective analysis investigated attainment/maintenance of major cytogenetic response (MCyR) by Months 3, 6, 9, and 12 as an early predictor of long-term outcomes in pts receiving bosutinib as second-line (CP 2L; after failure of IM only) or third/fourth-line (CP 3L; after failure of IM plus DAS and/or NIL) therapy for CP CML. Pts aged 318 y with CP CML received oral BOS starting at 500 mg/d. A total of 288 CP 2L pts with IM resistance (n = 200) or intolerance (n = 88) were enrolled: 53% were male, median age was 53 y (range, 18–91 y), and median time from CML diagnosis was 3.6 y (range, 0.1–15.1 y). A total of 119 CP 3L pts were enrolled following failure of IM plus resistance to DAS (n = 38), intolerance to DAS (n = 50), resistance to NIL (n = 27), intolerance to NIL (n = 1), or resistance/intolerance to DAS and NIL (n = 3): 45% were male, median age was 56 y (range, 20–79 y), and median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median treatment duration was 22.1 mo (range, 0.2–60.8 mo) for CP 2L pts and 8.6 mo (range, 0.2–60.8 mo) for CP 3L pts. Time from the last enrolled pt's first dose to the data cutoff was 23 mo for CP 2L pts, with a median follow-up duration of 31.8 mo (range, 0.6–66.0 mo). Time from the last pt's first dose to the data cutoff was 25 mo for CP 3L pts, with a median follow-up duration of 31.4 mo (range, 0.3– 66.0 mo). Among the 266 CP 2L pts who had a valid baseline cytogenetic assessment, a MCyR was attained/maintained (improved baseline cytogenetic assessment and attained a MCyR, or maintained baseline MCyR post-baseline) by 108/186 (58%) IM-resistant and 49/80 (61%) IM-intolerant pts, including 85/186 (46%) and 43/80 (54%) pts, respectively, who attained/maintained a complete cytogenetic response (CCyR). Among pts without a CCyR at baseline, 103/181 (57%) IM-resistant and 39/69 (57%) IM-intolerant pts achieved a MCyR. The Kaplan-Meier probability of maintaining a MCyR at 2 y was 71% for IM-resistant and 88% for IM-intolerant pts. Among 110 CP 3L pts who had a valid baseline cytogenetic assessment, cumulative rates for attaining/maintaining a MCyR and CCyR were 41% and 32%, respectively. The Kaplan-Meier probability of maintaining a MCyR at 2 y was 71%. A landmark analysis showed that the attainment/maintenance of a MCyR by Months 6, 9, and 12 on treatment was associated with an increased likelihood of overall survival (OS) at 2 y for both CP 2L and CP 3L pts. The difference in OS between those with and without a MCyR reached significance by Month 3 for CP 2L pts but not until Month 6 for CP 3L pts (Table). In conclusion, early attainment or maintenance of a MCyR (by Month 3) correlated with better OS in CP CML pts treated with BOS following IM failure. In CP CML pts treated with BOS following failure of 32 TKIs, 2-y OS was not different in pts with and without a MCyR prior to the Month 6 time point. This suggests that it is acceptable to allow longer periods of treatment for these pts to achieve responses without imparting significant long-term detriment. MCyR No MCyR n evaluablea MCyR, n OS at 2 yb (95% CI) No MCyR, n OS at 2 yb (95% CI) P value for OSc CP 2L cohort By Month 3 282 96 98% (91.8–99.5) 186 88% (82.0–91.8) 0.005 By Month 6 277 126 97% (91.7–98.8) 151 88% (82.0–92.6) 0.011 By Month 9 275 141 96% (91.5–98.5) 134 89% (81.7–92.9) 0.009 By Month 12 272 151 96%(91.3–98.2) 121 90% (82.8–94.1) 0.016 CP 3L cohort By Month 3 115 28 88% (68.1–96.1) 87 86% (75.9–91.5) 0.232 By Month 6 112 40 92% (77.4–97.4) 72 84% (73.2–90.9) 0.027 By Month 9 108 40 95% (80.1–98.6) 68 88% (76.9–93.6) 0.022 By Month 12 103 40 95% (81.0–98.7) 63 89% (77.7–94.4) 0.023 a Pts known to be alive exceeding the respective landmark time point. b Kaplan-Meier estimate of OS is based on total follow-up of 2 y from first BOS dose (response by Month 3 and OS over next 21 mo; response by Month 6 and OS over next 18 mo; response by Month 9 and OS over next 15 mo; or response by Month 12 and OS over next 12 mo). c Kaplan-Meier log-rank test for comparison of pts attaining/maintaining a MCyR versus no MCyR. Disclosures: Cortes: Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Hochhaus:Pfizer, Novartis, BMS, MSD, Ariad: Consultancy, Research Funding. Apperley:BMS, Teva, Ariad: Membership on an entity's Board of Directors or advisory committees; Pfizer, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis and BMS: Speaker at satellite symposia, Speaker at satellite symposia Other. O'Brien:Pfizer Inc: Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Ruffner:Pfizer Inc: Employment. Kantarjian:Pfizer Inc: Research Funding.

Long-Term Follow-up of a Phase 2 Study of Single Agent Lenalidomide in Previously Untreated, Symptomatic Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 718-718
Author(s):  
Christine Chen ◽  
Harminder Paul ◽  
Trina Wang ◽  
Lisa W Le ◽  
Vishal Kukreti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 718 Introduction: In a previously reported phase 2 study of single agent lenalidomide in 25 untreated CLL patients (pts), we reported an overall response rate (ORR) of 56% (14 pts), 40% SD (10 pts) and no CR at a median follow-up of 20.7 months (Chen et al. JCO 2010;29:1175). Although an amended protocol with conservative lenalidomide dosing was used to mitigate tumor lysis and severe myelosuppression observed in the first 2 accrued pts, we continued to observe frequent toxicities of grade 3–4 neutropenia (72%) and tumor flare (TF 88%). We now report long-term efficacy and toxicity from this study at a median follow-up of 47 months (mos). Methods: Patients were eligible if previously untreated and symptomatic (cytopenias, symptomatic adenopathy/organomegaly, constitutional symptoms, lymphocyte doubling count <12 mos). The amended starting dose for lenalidomide was 2.5mg daily on days 1–21 of a 28 day cycle, with slow monthly dose escalations (2.5mg cycle 1, 5mg cycle 2, 10mg cycle 3 and if required for response, further 5mg increments to a maximum of 25mg daily were allowed). Results: Longterm toxicities: Hematologic toxicities were common: grade 3–4 neutropenia (76%), thrombocytopenia (28%), anemia (20%). With longer term use, neutropenia tended to recur (12% of all cycles) and 10 pts required GCSF support (5 routinely during each cycle). Most common non-hematologic toxicities (all grades) were TF (88%), fatigue (76%), rash (60%), muscle cramping (40%), diarrhea (40%). All non-hematologic toxicities were mild (grade 1–2), except for 1 pt each with grade 3 rash and diarrhea. Although TF was most common during cycle 1, repeat flare symptoms upon resuming lenalidomide after the 7 day rest period of each cycle were noted in 16% of all 898 cycles administered, and as late as at cycle 28. Infections were mild (most respiratory, skin) with only 2 grade 3 events (disseminated zoster, S.pneumoniae bacteremia). Other malignancies: 2 pts developed transformed large cell lymphoma 7 and 18 mos after study discontinuation, 1 pt developed squamous cell carcinoma of skin at cycle 51, and 1 pt developed recurrence of remote non-small cell lung cancer at cycle 34. Dose modifications/discontinuation: The median highest dose achieved for all 25 pts was 15 mg (range 2.5–25 mgs); 8 pts were able to escalate to the maximal 25mg dose. Ten pts (40%) required dose reductions for grade 3 cytopenias [neutropenia (2), thrombocytopenia (2), both (2)], febrile neutropenia (2), and diarrhea (2). Of all 25 pts, the median duration on therapy was 31.1 mos (range 28 days – 60.6 mos). Twelve pts (52%) currently remain on study, receiving a median of 59 cycles of therapy (range 48–66). Causes of discontinuation for 13 pts included: treatment-related toxicity (8), lack of response/progressive disease (4), and recurrence of remote lung cancer (1). Toxicities leading to discontinuation included: prolonged cytopenias (3), recurrent infections (1), atrial fibrillation (1), disseminated herpes zoster (1), persistent grade 2 diarrhea (1), and grade 3 skin rash (1). Efficacy: With extended median follow-up from 20.7 to 47 mos, the ORR improved from 56% (14 pts) to 72% (18 pts), with 3 pts in PR upgrading to CR, and 1 SD to PR. Although the median time to response was 7.7 mos, responses occurred as quickly as 1.8 mos to as late as 27.0 mos of therapy. For the 3 CR pts, prolonged therapy with an additional 14.9, 28.3 and 40.6 mos beyond the time of first response was required to achieve CR. To date, 7 pts have progressed with 3-year PFS 68.8% (95% CI:52–91%) and OS 85.3% (95% CI:71.1–100%). Correlatives: Cereblon (CRBN), recently identified as a direct protein target of lenalidomide, was evaluated by gene expression profiling and Western blot and found to be uniformly expressed in all 19 evaluable day 1 pt samples regardless of lenalidomide response. Thus, baseline CRBN expression does not appear to be a useful predictive biomarker of response in this population. The mechanism by which CRBN is linked to response is reported by Trudel et al, ASH 2012. Conclusions: Long-term followup of this study demonstrates that when using low doses of single agent lenalidomide in CLL, prolonged therapy is feasible and may be required for the achievement of durable, high quality responses. Maximal daily doses of 25mg can be reached and may also be needed for optimal response, though recurrent myelosuppression remains limiting. Disclosures: Chen: Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Lundbeck: Consultancy; Janssen: Consultancy, Research Funding. Off Label Use: Lenalidomide is not approved for use in chronic lymphocytic leukemia. Kukreti:Roche: Honoraria; Celgene: Honoraria; Janssen Ortho: Honoraria. Trudel:Celgene: Honoraria, Research Funding, Speakers Bureau.

Multivariate Analysis Identifies Significant Correlations Between Baseline Biomarkers, DNA Demethylation and Clinical Responses in 122 Patients Treated in a Phase 1/2, Study of Guadecitabine (SGI-110), in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia (r/r AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2594-2594 ◽  
Author(s):  
Srikanth Gottipati ◽  
Shashank Rohatagi ◽  
Woonbok Chung ◽  
Pietro Taverna ◽  
Hagop M. Kantarjian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multivariate Analysis ◽  
Clinical Response ◽  
Phase 1 ◽  
Dna Demethylation ◽  
Integrated Analysis ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Pharmaceutical Development ◽  
Clinical Responses

Abstract Introduction: Guadecitabine (SGI-110) is a novel subcutaneous (SC) next generation hypomethylating agent (HMA) designed as a dinucleotide of decitabine (DAC) and deoxyguanosine that is resistant to degradation by cytidine deaminase (CDA) and results in prolonged in vivo exposure to its active moiety DAC. The differentiated pharmacokinetic profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. In the Phase 1 study, patients with r/r AML were treated at escalating doses of guadecitabine. In the phase 2 study, r/r AML patients were randomized to receive guadecitabine at 60 mg/m2 or 90 mg/m2 SC daily for 5 days (dailyx5). In a separate cohort, patients were treated with 60 mg/m2 SC daily for 10 days (dailyx10: days 1-5 and 8-12) for up to 4 cycles followed by subsequent cycles of the dailyx5 regimen. All regimens were dosed with a 28 day treatment cycle. We have reported the clinical efficacy and safety results from the Phase 1 dose-escalation study in AML and MDS (Issa et al, Lancet Oncology 2015) and the Phase 2 randomized dose-response study in r/r AML at 2 doses (60 and 90 mg/m2) in a 5-day regimen (Kantarjian et al, ASH 2013) and 60 mg/m2 in the 10-day regimen (Griffiths et al, ASCO 2014). Here, we report the associations between clinical responses and global DNA demethylation assessed by LINE1 assay, baseline expression of a panel of 7 genes (CDA, P15, P21, DNMT3B, DNMT3A, DNMT1 and CTCF) assessed by qRT-PCR, and FLT3-ITD/NMP1 mutations. Methods: Samples from 122 patients with r/r AML were analyzed (27 from phase 1 study treated at 36 m/m2/d or higher, 47 from the dailyx5 and 48 from the dailyx10 regimen of the phase 2). Global DNA methylation at baseline and after treatment, were estimated using bisulphite-pyrosequencing on the LINE-1 repetitive sequence for assessing guadecitabine pharmacodynamic (PD) effects. LINE-1 methylation time-course profiles were available in 117 out of 122 analyzed patients. Multivariate analysis was performed using nonlinear ensemble decision tree-based classification algorithms (Random Forests and Gradient Boosting Trees); the algorithms were applied to rank demographic features, treatment schedule features, baseline expression of 7 genes, FLT3-ITD and NPM1 mutations, LINE-1 methylation profiles and baseline hematological features as predictors of clinical response and to measure their directionality. All reported percentages are a measure of the average relative contribution of each feature in predicting response across boosted trees and are normalized across features. Results: In the 122 patients analyzed, the median age was 59.6 (range, 23-86), 75 were males (61.5%). Overall, peak LINE-1 demethylation generally occurred on day 8 after daily x 5 treatment or on day 8 or 15 after daily x 10 treatment. Overall, the maximum peak LINE-1 demethylation was -23.8 % ± 1.24. In 122 r/r AML patients, 28 showed Complete Response (23%, 14 CR and 14 CRi/CRp). High baseline CDA gene expression in peripheral blood was consistently ranked the main predictor of clinical response (mean for responders~1.76 and non-responders~0.12) irrespective of patient gender, dose and dosing cycles, and contributed for 22% of the model accuracy in predicting responses to guadecitabine. Expression of the genes CTCF (11%), DNMT3B (7%) and P21 (6%) were other genes that contributed > 5% in predicting clinical response. Age (8%) was also a significant predictor of response. FLT3-ITD mutations and NPM1 mutations were not significant predictors of response. In an integrated analysis, where methylation levels and gene expression were ranked together on their power to predict clinical response, LINE-1 methylation percent change from baseline on days 8(6%) and 22(19%), age (16%), CTCF (9%), CDA(7%), P21(6.5%) gene expression at baseline had greater than 5% contribution in predicting clinical response. A similar analysis was then performed to rank features on their power to predict day 8 methylation; CDA (28%), DNMT1 (8.5%), P15 (7.5%), and CTCF (7%) gene expression at baseline and age (7%) had greater than 5% predictive power. Conclusions: In conclusion, in r/r AML patients, global DNA demethylation was strongly associated with clinical responses to guadecitabine and analysis of baseline gene expression can identify trends that might enrich for r/r AML patients more likely to respond to HMA therapy with guadecitabine. Disclosures Gottipati: Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Rohatagi:Otsuka Pharmaceutical Development & Commercialization, Inc.: Employment. Chung:Astex Pharmaceuticals, Inc.: Research Funding. Taverna:Astex Pharmaceuticals, Inc.: Employment. Kropf:Teva Pharmaceuticals: Consultancy. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Astex Pharmaceuticals, Inc.: Consultancy; Janssen: Consultancy.

scholarly journals Rituximab Plus Bendamustine and Cytarabine (R-BAC) in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma: Long Term Follow-up and Mrd Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 384-384
Author(s):  
Maria Chiara Tisi ◽  
Luca Nassi ◽  
Caterina Patti ◽  
Michele Spina ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Mantle Cell

Abstract The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes. After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p&lt;0.05), elevated Ki67 &gt; 30% (p&lt;0.05), and failure to achieve CR after 2 cycles (p=0.03). Early-progression of disease (&lt;24 months from start of R-BAC) was associated with impaired overall survival (p&lt;0.05). Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia. Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses. As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p&lt;0.05 for them both). In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL. Figure 1 Figure 1. Disclosures Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.

scholarly journals Updated Safety and Efficacy Results of Phase 1 Study of Olverembatinib (HQP1351), a Novel Third-Generation BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI-Resistant Chronic Myeloid Leukemia (CML)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 311-311
Author(s):  
Jiang Qian ◽  
Dayu Shi ◽  
Zongru Li ◽  
Yazhen Qin ◽  
Ting Zhao ◽  
...  
Keyword(s):  
Adverse Event ◽  
Research Funding ◽  
Phase 1 ◽  
Third Generation ◽  
Publicly Traded ◽  
Safety And Efficacy ◽  
Grade 3 ◽  
Cutoff Date

Abstract Background: Management of CML using TKIs is often constrained by treatment resistance, which portends a poor prognosis. Treatment failure may be due to therapeutic resistance (BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I ("gatekeeper") genotype is insensitive to first- and second-generation TKIs, while compound mutations complicate management with all TKIs (including third-generation TKI ponatinib). HQP1351 (olverembatinib) is a novel, third-generation, orally active BCR-ABL1 TKI with evidence of antitumor activity against CML regardless of genotype (Ren X et al. Med Chem 2013;56:879-94) and a preliminary favorable safety profile in clinical trials (Jiang Q et al. Blood 2020;136:50-1). Methods: This Chinese, open label, multicenter, phase 1 trial evaluated the safety and efficacy of olverembatinib in adults with CML in chronic phase (CML-CP) or accelerated phase (CML-AP). Eligible patients have CML-CP or CML-AP that is resistant or intolerant to first- or second-generation TKIs. Patients with severe cardiovascular diseases, hypertension, and pulmonary arterial hypertension were excluded. Olverembatinib is orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg. This study reports data on patients with long-term follow-up. Results: From October 26, 2016, through February 2, 2021 (data cutoff date), 101 patients with CP-CML (n = 86) and AP-CML (n = 15) were enrolled and treated with olverembatinib. Seventy-one (70.3%) patients were male, the median age was 40 (range, 20-64) years, and median (range) interval from diagnosis to initial olverembatinib treatment was 6.0 (0.3-15.2) years. Eighty-four (83.2%) patients received ≥ 2 prior lines of TKI-therapy, and 63 (62.4%) harbored T315I mutation. At baseline, compound mutations were detected in 11 (10.9%) patients, of whom 7 (63.6%) had the BCR-ABL1 T315Igenotype. A total of 20 (19.8%) patients had 2 (n = 13) or ≥ 3 (n = 7) mutations. The median follow-up was 30.8 (1.2-51.8) months. As of the data cutoff date, 81 (80.2%) of 101 patients continued on treatment and 20 (14 CP-CML and 6 AP-CML) discontinued because of disease progression, intolerance, or occurrence of a secondary cancer. The cumulative median (range) drug exposure was 13,635 (1,650-20,975) mg. Of 101 patients, 18 (17.8%) were treated for &gt; 3 years and 5 (5%) for &gt; 4 years. Of evaluable patients without baseline responses, 97.0% had complete hematologic responses (CHR), 62.1% complete cytogenetic responses (CCyR), and 51.0% major molecular responses (MMR). Most evaluable patients with T315I mutations experienced 100% for CHR, 83.7% for MCyR, and 71.2% for MMR among patients in CP-CML, as well as 80.0% for CHR and 54.5% each for MCyR and MMR in AP-CML. At 36 months, the PFS rate (95% CI) was 96.3% (89.1%-98.8%) in patients with CP-CML and 71.4% (40.6%‒88.2%) in those with AP-CML. Treatment responses were durable and unaffected by baseline BCR-ABL1 mutational status. Corresponding values in patients with &gt; 4 years of treatment were 100% (CHR), 80% (CCyR), and 60% (MMR). The mean (95% confidence interval) PFS rate was 100% (100%-100%) at 36 months, 100% at 48 months, and not reached (NR-NR) at 60 months. Most treatment-related adverse events were grade 1 or 2. The most frequent nonhematologic adverse event was (mostly grade 1 or 2) skin hyperpigmentation (86.1%). Grade ≥ 3 nonhematologic AEs included hypertriglyceridemia (10.9%), pyrexia (6.9%), and proteinuria (5.0%). The most common hematologic treatment-related adverse event was thrombocytopenia in 78 (77.2%) patients, including 52 (51.5% of total population) with grade ≥ 3 and 6 (5.9%) with serious adverse events. Leukopenia was grade ≥ 3 in 21 (20.8%) patients but not serious, while anemia was grade 3 or higher in 16 (15.8%) patients and serious in 4 (4.0%). Conclusions: In patients with TKI-resistant CML-CP or CML-AP and long-term treatment, olverembatinib was efficacious and well tolerated. Internal study identifier HQP1351-SJ002. Figure 1 Figure 1. Disclosures Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Wang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

scholarly journals Gene Therapy for Fanconi Anemia, Complementation Group a: Updated Results from Ongoing Global Clinical Studies of RP-L102

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Agnieszka Czechowicz ◽  
Rajni Agarwal ◽  
Julián Sevilla ◽  
Paula Río ◽  
Susana Navarro ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bone Marrow ◽  
Fanconi Anemia ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Medicinal Products ◽  
Publicly Traded ◽  
Hematopoietic Stem

Background: Fanconi anemia (FA) is a rare inherited disorder of defective cellular deoxyribonucleic acid (DNA) repair, associated with developmental abnormalities and characterized by progressive bone marrow failure (BMF) and a predisposition to hematologic malignancies and solid tumors. Approximately 60-70% of all cases result from mutations in the Fanconi Anemia Complementation Group A (FANCA) gene (FA-A). 80% of FA patients develop BMF within the first decade of life. Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potentially curative treatment for BMF, its utilization and efficacy are limited by availability of suitable human leukocyte antigen (HLA)-matched donors, risk of graft-versus-host disease (GVHD) and transplant-related toxicities. Ex-vivo lentiviral mediated gene therapy of autologous FA-A CD34+ enriched hematopoietic stem and progenitor cells (HSPCs) has been shown to confer a survival advantage to gene-modified HSPCs in preclinical studies and, most recently, in the investigator initiated Phase 1/2 FANCOLEN-I clinical trial conducted in Madrid, Spain. Based on the highly favorable safety profile and promising preliminary efficacy data, global studies using "Process B" optimization including transduction enhancers, commercial-grade vector, and modified cell processing are underway. Herein, we report updated results from the US Phase 1 clinical trial and preliminary data from the global Phase 2 study in US and EU. Design and Methods: Subjects with a confirmed FANCA gene mutation aged 1 year or older, with no HLA-matched sibling donor and at least 30 CD34+ cells/µL in bone marrow (BM) were eligible for enrollment. Peripheral blood (PB) mononuclear cells were collected via leucocytapheresis on two consecutive days after mobilization with granulocyte-colony stimulating factor (G-CSF) and plerixafor. CD34+ HSPCs were enriched, transduced with a lentiviral vector (PGK-FANCA-WPRE) and infused fresh (not cryopreserved) without any antecedent conditioning. Patients are being followed for 3 years post-infusion for safety assessments (replication competent lentivirus (RCL), insertion site analysis (ISA)) and to ascertain evidence of efficacy (increasing PB vector copy number (VCN) and BM mitomycin-C (MMC) resistance), along with stabilization/correction of cytopenias. Results: As of August 2020, 2 subjects (aged 5 and 6 years) have received RP-L102 infusion on the Phase 1 study with over 12 months of follow up. Preliminary evidence of gene marking in PB post-RP-L102 infusion at various timepoints has been observed in both subjects. Increased bone marrow (BM) mitomycin-C (MMC) resistance post treatment has also been identified in at least 1 subject. Subject L102-001-1001 has had blood count stabilization over the 12 months following gene therapy administration. Subject L102-001-1002's course has been complicated by influenza B infection with concomitant decreases in blood counts requiring red blood cell transfusions. Transfusion requirements have decreased following resolution of infection. Since November 2019, 5 additional subjects have been enrolled onto the global Phase 2 study and received investigational infusion. Updated preliminary safety and efficacy data including PB VCN, blood counts and BM MMC resistance will be available at the time of presentation for subjects with over 12 months of follow up; drug product (DP) information (VCN and CD34+ cell dose) will be available for all treated subjects. Conclusions: DP has been successfully manufactured in the Phase I (N=2) and Phase 2 (N=5) to meet the required specificationsSafety profile of RP-L102 continues to be highly favorable.Evidence of engraftment has been seen in at least 1 subject with follow up of at least 12 months as indicated by PB genetic markings and increasing BM CFC MMC resistance; 12+ months of follow-up may be required to observe the proliferative advantage of transduced HSPCs. Disclosures Czechowicz: Rocket Pharmaceuticals, Inc.: Research Funding. Sevilla:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Río:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: PR has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Navarro:Rocket Pharmaceuticals, Inc.: Current equity holder in publicly-traded company, Other: SN has licensed medicinal products and receives research funding and equity from Rocket Pharmaceuticals, Inc., Patents & Royalties, Research Funding. Beard:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Law:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Choi:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zeini:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Nicoletti:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Wagner:BlueRock: Research Funding; Magenta Therapeutics: Consultancy, Research Funding; Gadeta: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company. Schwartz:Rocket Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Bueren:Rocket Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company, Other: Consultant for Rocket Pharmaceuticals, Inc. and has licensed medicinal products and receives research funding and equity from this company., Patents & Royalties, Research Funding.

Safety of TG-C: 12 years of follow-up safety data from phase 1, phase 2, ongoing phase 3, and long term safety trials

2021 ◽  
Vol 29 ◽  
pp. S253-S254
Author(s):  
D. Hunter ◽  
A. Mobasheri ◽  
S. Mareya ◽  
M. Wang ◽  
H. Choi ◽  
...  
Keyword(s):  
Phase 1 ◽  
Safety Data ◽  
Phase 2 ◽  
Phase 3 ◽  
Ongoing Phase
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